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WO2003006061A1 - Compositions de medicaments pour usage ophtalmologique - Google Patents

Compositions de medicaments pour usage ophtalmologique Download PDF

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Publication number
WO2003006061A1
WO2003006061A1 PCT/JP2002/007088 JP0207088W WO03006061A1 WO 2003006061 A1 WO2003006061 A1 WO 2003006061A1 JP 0207088 W JP0207088 W JP 0207088W WO 03006061 A1 WO03006061 A1 WO 03006061A1
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Prior art keywords
propyl
amino
pharmaceutical composition
adrenergic receptor
ethyl
Prior art date
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PCT/JP2002/007088
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English (en)
Japanese (ja)
Inventor
Kenji Muta
Ichiro Hirotsu
Hiroshi Miyata
Makio Kitazawa
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Kissei Pharmaceutical Co Ltd
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Kissei Pharmaceutical Co Ltd
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Priority to EP02745996A priority Critical patent/EP1415666A4/fr
Priority to CA002453476A priority patent/CA2453476A1/fr
Priority to US10/483,650 priority patent/US20040235932A1/en
Publication of WO2003006061A1 publication Critical patent/WO2003006061A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to a novel ophthalmic pharmaceutical composition. More specifically, the present invention relates to an ophthalmic pharmaceutical composition containing at least one ⁇ 1 ⁇ -adrenergic receptor neutral antagonist as an active ingredient.
  • Glaucoma a disease of the ophthalmology field, is a disease in which visual function is impaired due to increased intraocular pressure, which is caused by birth defects, secondary to various eye diseases, trauma, surgery, etc., and a genetic predisposition And glaucoma causing abnormalities in the aqueous humor outflow channel from corners due to structural changes.
  • glaucoma can occur at various ages from newborns to the elderly, early treatment including prevention is necessary as one of the most common adult diseases that lead to blindness after middle age.
  • adrenergic receptor hereinafter referred to as “hi-i-AR”
  • hi-i-AR an adrenergic receptor
  • i1AR has been identified as ⁇ 1 ⁇ -adrenergic receptor subtype (hereinafter referred to as o; 1A- AR) and ⁇ 1 ⁇ -adrenergic receptor.
  • subtype hereinafter, alpha 1 beta - AR hereinafter
  • o 1 D - Adorenarin
  • the presence of three subtypes of receptor subtypes is confirmed, their subtypes, various animal and human various organs Localization and function has also been widely studied.
  • the iris of the rabbit alpha 1 Alpha - is reported and child present advantage is AR (.. British Journal of Pharmacology , Vol 127, No.
  • G protein-coupled receptors such as jS-adrenergic receptor and histamine receptor, including one adrenergic receptor, exist in a certain equilibrium state between the inactive type and the active type “I”, and the active type It has been reported that only pharmacokinetics cause physiological responses through intracellular signaling systems such as protein kinase C (Pharmacol. Rev., Vol. 48, pp. 413-463 (1996); Trends Pharmacol. Sci., Vol. 16, pp. 89-97 (1995)) On the other hand, studies are also being conducted on the effects of agonists and antagonists on these receptors, and most of the general antagonists are inactive and active forms of the receptors.
  • H 2 -histamine known as a therapeutic agent for gastric 'duodenal ulcer' cimetidine and ranitidine receptor Antagonisuto is strongly Inbasu Agonisuto Katsusei, these H 2 - histamine receptor antagonist with long-term use H 2 - histamine receptor number increases, resulting in the development of resistance (action attenuation) . and used it interrupted causing Ribaundo phenomena such as gastric acid hypersecretion due have been pointed out as a problem H 2 - other histamine receptor
  • Glaucoma requires long-term intraocular pressure control. Strong agonist activity: If you continue to use Nist treatment, drug resistance, which reduces the action of antagonist, and rebound phenomenon, which worsens the symptoms if you withdraw from the drug, are likely to occur. Problems have been pointed out, such as increased side effects due to the necessity of increasing the amount of the drug delivered, and also significant or complete loss of efficacy.
  • the Q-AR antagonist corinacin (17 ⁇ -hydroxyyohimban- 16 J3-methyl ribonate) is a disease associated with abnormal intraocular pressure in which the average intraocular pressure exceeds
  • an intraocular hypotensive effect was observed in the drug concentration of 2 to 5%, but it was reported that drug resistance developed after one week of continuous administration (Ophthalmology, Vol. 92, No. 7, pp. 977-980 (1985)).
  • bunazosin hydrochloride (1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -1,4-butylinolehexahydro-1H-1,4-diazepine hydrochloride) is a drug.
  • a drug is a drug.
  • resistance is unlikely to occur, in clinical trials for patients with primary open-angle glaucoma (chronic primary glaucoma) and ocular hypertension, 0.05% drug concentration for 4 weeks in the ophthalmic group
  • the treatment of ophthalmic disorders is usually long-lasting, and the development of drug resistance of the ocular hypotensive used is a significant problem in treatment: Continual use of the drug attenuates the effect of lowering intraocular pressure, and increasing the amount used is expected to increase the incidence of drug resistance. Disclosure of the invention
  • An object of the present invention is to treat ophthalmic diseases, particularly glaucoma or ocular hypertension, which can suppress the development of drug resistance due to continuous use, can be used continuously for a long time, and can be applied to a wide range of patients.
  • Another object of the present invention is to provide an excellent pharmaceutical composition effective for prevention.
  • the present inventors in order to develop and effective therapeutic agent for glaucoma not express drug resistance were conducted various o ⁇ -AR antagonist diary study results, o; 1 A - for AR Antagonists with no or very low inverse agonist activity were found.
  • the present invention is based on this finding.
  • ⁇ 1 ⁇ - Adorenarin ophthalmic medicament characterized in that it contains a receptor neutral antagonist as an active ingredient, SoNarubutsu, preferably Wahi l [alpha] - Adorenarin receptor neutral antagonist force general formula:
  • ⁇ is a lower alkylene group
  • R is a lower alkyl group or a halo lower alkyl group
  • Y is an ethylene group or a vinylene group.
  • Is selected from the compounds represented by the following formulas , prodrugs thereof, and pharmaceutically acceptable salts thereof, and more preferably ⁇ 1 ⁇ -adrenergic receptor neutral antagodist is represented by (R) —5— [2— [ [2- (2-Ethoxyphenoxy) ethyl] amino] propyl] 111- (3-hydroxypropyl) 111-indole-1-71 carboxamide, (R) -1- (3-hydroxypropyl ) -5- [2-[[2-1- [2 -— (2,2,2-triphnoleo-ethoxy) phenoxy] ethynole] amino] propinole] 1 1-indole-17-caprolupoxamide, their prodrugs, and
  • the prodrug is selected from those pharmaceutically acceptable salts, and the prodrug is pivalic acid (R) —3— [7—potumbamoyl-1-5- [2 -— [[2- (2-ethoxyethoxyen
  • ⁇ ; 1 ⁇ -adrenergic receptor 2 eutranore antagonist has the general formula:
  • ⁇ is a lower alkylene group
  • R is a lower alkyl group or a halo-lower alkynole group
  • Y is an ethylene group or a vinylene group
  • a Q! 1A -adrenergic receptor neutral antagonist preferably ⁇ 1 ⁇ -adrenergic receptor neutral antagonist, for the manufacture of a pharmaceutical composition for treating or preventing glaucoma or ocular hypertension.
  • ⁇ is a lower alkylene group
  • R is a lower alkyl group or a halo lower alkynole group
  • Y is an ethylene group or a vinylene group
  • Figure 1 shows intracellular I in ai A — AR (mutant and wild type) expressing CHO cells.
  • a unmutated - is a graph showing the effect of each of the test drugs on receptor expression level in AR-expressing CHO cells.
  • the vertical axis indicates ⁇ 1 ⁇ -AR expression level (fmolZmg protein), and the horizontal axis indicates the presence or absence and the type of test drug.
  • Hi 1 A a pharmaceutical composition containing an AR neutral antagonist as an active ingredient
  • the present invention relates to an ophthalmic pharmaceutical composition, particularly a pharmaceutical composition for treating or preventing glaucoma or ocular hypertension disease, comprising a 1A- AR neutral antagonist as an active ingredient. .
  • a 1A —AR neutral antagonist or “ ⁇ 1 ⁇ —adrenergic receptor neutral antagonist” refers to an antagonist that does not increase the number of receptors even if used for a long time, or even if used for a long time.
  • Attenuated action Means an antagonist to ⁇ 1 ⁇ -AR that does not cause drug resistance or rebound phenomenon that worsens symptoms after withdrawal .
  • neutral antagonists are the inactive and active forms of the receptor. Does not affect the equilibrium state of While antagonist, which has a strong inverse agonist activity, is prone to drug resistance due to continuous use and a rebound phenomenon that worsens the symptoms if the drug is withdrawn, neutral antagonists are used in such invaginated sagonists. For neutral antagonists, see Pharmacia, Vol. No. 6, pp. 617-621 (1997), but no details have been reported so far, including its mechanism of action.
  • “o; 1A— AR neutral antagonist” has extremely low inverse agonist activity as measured by the inverse agonism activity measurement method described in the present specification or a similar method.
  • 1A very little and little or no increase in AR number, ie very low or substantially no inverse agonist activity o; also includes antagonists to 1A _AR I do.
  • the measurement of the inverse agonist activity can be performed by the method using the mutant type 1A -AR described in Example 1 below, or by a method equivalent thereto. Briefly, a 1A - fin Perth ⁇ Gore Marianist activity against the AR, inositol -1, 4, 5-triphosphate (hereinafter, referred to as IP 3) is confirmed by ⁇ pressurized production amount or number of receptors in the be able to. IP 3 is one of the intracellular messengers generated during the activation of protein kinase C.
  • a 1A -AR Substances that are neutral antagonists can be screened.
  • CHO cells expressing mutant type 1A -AR in which the active form is dominant can be prepared by methods described in the literature (British Journal of Pharmacology, Vol. 127, pp. 962-968 (1999); British Journal of Pharmacology, Vol. 131, pp. 546-552 (2000)).
  • one candidate substance is a 1A —AR neutral antago
  • Facial i A - can be determined by comparing the change in the number of AR.
  • the active ingredient of the present composition "alpha l [alpha] - AR neutral antagonist", o with hydrochloric acid Bunazo thin presence is an inverse ⁇ Gore Marianist; 1A - when the AR increased 1, about It is 1Z3 or less, preferably about 1.6 or less, more preferably substantially zero.
  • Such a method involves culturing cells expressing a mutant ⁇ 1 ⁇ -adrenergic receptor in which the active form is dominant together with an ⁇ -adrenergic receptor eutranal antagonist, and increasing the receptor.
  • a method for screening a substance which does not substantially exhibit drug resistance, which is used for ophthalmology, particularly for preventing or treating glaucoma or ocular hypertension disease, characterized in that it is determined whether or not the drug is acting on the subject.
  • a screening method which further comprises comparing with the increased number of the receptor in an ophthalmic inverse agonist, for example, bunazosin hydrochloride. Such a screening method may also form part of the present invention.
  • any a 1A being win ophthalmically acceptable - AR neutral antagonist can be contained as an active ingredient of the present compositions.
  • the Q! 1A -AR neutral antagonist used in the present invention includes, for example, the following general formula (I):
  • A is a lower alkylene group
  • R is a lower alkyl group or a halo-lower alkyl group
  • Y is an ethylene group or a vinylene group
  • the lower alkylene group in the substituent A is, for example, a straight or linear alkyl group having 2 to 6 carbon atoms such as an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. It is a branched alkylene group (however, the bonding position of the hydroxy group bonded to the substituent A is other than the ⁇ ; position).
  • the lower alkyl group for R is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butylinole group, a pentynole group, an isopentyl group, a neopentyl group, a 1-methylbutyl group, It is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms such as a 2-methynolebutyl group and a hexyl group.
  • the lower alkyl group is, for example, a trifluoromethyl group, a trifluoroethyl group, etc.
  • the a 1A -AR neutral antagonist used in the present invention is (R) -5- [2-[[2- (2-ethoxyphenoxy) ethyl] amino] propyl] —1— (3— (Hydroxypropyl) 1 H-indole-1 7-carboxamide, (R) -1 (3-hydroxypropyl) -5- [2-[[2- [2-]
  • 1A _AR Yuyutora Le antagonist may be used as it is active body, also be converted into the active body during and after corneal penetration or permeation Q! yo les, it is used as Purodora' grayed showing a 1A _AR antagonist activity.
  • Examples of the prodrug of the present invention include compounds in which various groups that can be appropriately used as a prodrug, such as a hydroxyl group and an imino group, are introduced into the compound represented by the general formula (I), and the prodrug can be used as a prodrug.
  • groups include, for example, drug development, Vol. 7, Molecular Design, 163-: L, page 98, published by Tokyo Hirokawa Shoten; Drugs of the Future, 16 (5), 443-458 (1991); drug bioavailability. Science of Evaluation and Improvement, 133-: L, p. 53, and various groups described in the literature such as published by Hyundai Medical Co., Ltd.
  • Pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and nitric acid.
  • Acid, acid addition salts with mineral acids such as phosphoric acid, carbonic acid, formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, citric acid, succinic acid, tartaric acid, fumaric acid, malonic acid, maleic acid, malic acid, lactic acid
  • Examples thereof include acid addition salts with organic acids such as adipic acid, benzoic acid, salicylic acid, methanesulfonic acid, p.-toluenesulfonic acid, glutamic acid, and aspartic acid.
  • Preferred prodrugs are pivalic acid (R) 13- [7-forcerubamoyl 5- [2-[[2- (2_ethoxyphenoxy) ethyl] amino] propyl] —1H-indole Propyl] or a pharmaceutically acceptable salt thereof (hereinafter, the hydrochloride is referred to as KRG—33332).
  • indole derivatives can be prepared by methods known in the art, or are commercially available.
  • the compound represented by the general formula (I), a prodrug thereof, or a pharmaceutically acceptable salt thereof is disclosed in the literature (JP-A-7-330725; JP-A-7-33). No. 0726 / WO; WO99 / 43652/95) or a method similar thereto. Briefly, for example, these compounds can be prepared by methods described in the literature or by methods analogous thereto.
  • the corresponding indolincarbonitrile derivatives are prepared using aqueous sodium hydroxide and hydrogen peroxide.
  • the product is produced by removing the nitrogen atom protecting group by oxidizing the indoline ring in the presence of a metal catalyst such as palladium carbon and ammonium formate. be able to.
  • the a 1 A —AR neutralizer antagonist contained as an active ingredient in the pharmaceutical composition of the present invention may be used as a pharmaceutically acceptable salt.
  • Such pharmaceutically acceptable salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, formic acid, acetic acid, propionic acid , Butyric acid, oxalic acid, citric acid, succinic acid, tartaric acid, fumaric acid, malonic acid, maleic acid, malic acid, lactic acid, adipic acid, benzoic acid, salicylic acid, methanesulfonic acid, ⁇ -toluenesulfonic acid, glutamic acid, asparagine Acid addition salts with organic acids such as acids And salts with organic bases such as 2-aminoethanol, piperidine, morpholine and pyrrolidine, and salts with inorganic bases such as sodium, potassium, calcium and magnesium
  • the ophthalmic pharmaceutical composition in the present invention means a pharmaceutical composition applicable to ophthalmic diseases.
  • “Glaucoma” as intended by the composition of the present invention broadly refers to a disease in which visual function is impaired due to increased intraocular pressure, regardless of the etiology such as birth defects, trauma, and surgery. Glaucoma usually has an average intraocular pressure of more than 2 ImmHg, but is also called normotensive glaucoma, in which glaucomatous changes are seen in the visual field and optic disc even if the average intraocular pressure is 21 mmHg or less This is also included in glaucoma in the present invention.
  • Ocular hypertension which is another disease targeted by the composition of the present invention, is a disease associated with abnormal intraocular pressure in which the average intraocular pressure exceeds 2 ImmHg.
  • ocular hypertension hypertensive disease
  • Ocular hypertension may develop into glaucoma even if there are no abnormalities in visual function. Proper treatment in is important from the perspective of glaucoma prevention. Therefore, a pharmaceutical composition used for an ocular hypertension disease is also included in the scope of the present invention.
  • a preferred pharmaceutical composition of the present invention comprises a compound represented by the above general formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and which does not increase the number of receptors even after long-term use. It is an ophthalmic pharmaceutical composition that does not cause drug resistance in which the antagonistic effect is attenuated even after long-term use or rebound phenomenon in which the symptoms are further exacerbated when the drug is withdrawn.
  • Eye drops and other pharmaceutical compositions can be manufactured according to conventional pharmacological techniques.
  • ophthalmic preparations and eye drops are prepared by adding the active ingredient of the present invention to sterile purified water, dissolving or suspending by adding an appropriate solubilizing agent, suspending agent, etc., as necessary.
  • tonicity agent pH adjustment It can be prepared by adding an agent, etc., and removing dust and bacteria.
  • the dose of the active ingredient o; 1A— AR-eutranal antagonist depends on the type of the active ingredient, the sex, age, weight, and disease of the patient.
  • the dose of the active ingredient o; 1A— AR-eutranal antagonist depends on the type of the active ingredient, the sex, age, weight, and disease of the patient.
  • the present invention provides a method for treating or preventing glaucoma or ocular hypertension, comprising administering to a patient in need thereof a therapeutically effective amount of an A -adrenergic receptor neutral antagonist. It also includes the method of (1).
  • the o! 1A -adrenergic receptor neutral antagonist used in this method is as described above.
  • the present invention also encompasses the use of a 1A -adrenergic receptor neutral antagonist for the manufacture of a pharmaceutical composition for treating or preventing glaucoma or ocular hypertension.
  • the 1 A -adrenergic receptor neutral antagonist used in the manufacture of this pharmaceutical composition is as described above.
  • the present invention also includes the pharmaceutical composition of the present invention used in combination with 1 A -AR inverse agonist (ie, an antagonist having high inverse agonist activity).
  • a pharmaceutical composition that also contains a 1A —AR inverse agonist ⁇ 1 —AR neutrinore antagonist.
  • “o; 1A— AR inverse agonist” is a substance which is liable to cause side effects such as a rebound phenomenon in which the antagonistic action is attenuated by continuous use as described above, and the symptoms are further exacerbated by drug resistance or withdrawal. is there. If the composition of the present invention is used in combination with an inverse agonist , ⁇ 1 ⁇ — 'These inconveniences are unlikely to occur, and the dose of o: 1A- AR inverse agonist can be kept low, which also makes the above-mentioned side effects unlikely to occur. Therefore, it is possible to obtain a highly safe formulation with less side effects that not only achieves an improvement in the therapeutic effect, but also maintains effective growth for a long time. The Q!
  • 1A -AR inverse agonist in the present invention is not particularly limited provided that it has a desired activity and is acceptable as an ophthalmic preparation.
  • bunazosin hydrochloride (1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -1,4-butyrylhexahydro-1H-1,4-diazepine hydrochloride), terazosin hydrochloride (1-1 (4-amino- 6,7-dimethoxy-l-quinazolinyl) 1-4- (tetrahydro-l-furoyl) pidazine hydrochloride dihydrate), doxazosin mesylate (l- (4-amino-6,7-dimethoxy-l-quinazolyl) (Ninore) 1-41 (1,4-Benzodioxane 1-2-ylcarbonyl) piradizine methanesnolephonate), ⁇ rabidinole (6 — [
  • bunazosin hydrochloride are commercially available, or various compounds are described in the following literature or based on Can be produced by the following method: International Publication WO 94/05628, JP-A-62-16417, JP-A-56-103177, US Pat. No. 5,993,911, JP-A-54-27588. JP-A-52-48678, JP-A-54-98792, U.S. Pat. No. 3,957,786, U.S. Pat. No. 4067982.
  • the composition containing Q! 1A -AR neutral antagonist of the present invention when used in combination with inverse ⁇ agonist, compositions containing these as a rule, will contain each Antagoni strike by an appropriate amount. Further, o!
  • the formulation may be prepared by a usual method, and the dosage may be appropriately adjusted at the time of application.
  • the formulation and preparation method of such a preparation are well known to those skilled in the art.
  • the present invention provides a method for treating glaucoma or ocular hypertension, comprising administering to a patient receiving A-adrenergic receptor inverse agonist a therapeutically effective amount of ⁇ 1 ⁇ -adrenergic receptor neutral antagonist. It also houses methods for treating or preventing the disease.
  • the TsutomuAkira for the manufacture of a pharmaceutical composition for treating or preventing glaucoma or ocular hypertension disease, alpha l [alpha] - Adorenarin receptor Neutral antagonists and alpha l [alpha] - adrenergic receptor Inbasu It also includes the use of agonists.
  • Pharmaceutical composition used as a neutral antagonist preferably (R) -5- [2-[[2- (2-ethoxyphenoxy) ethyl] amino] propyl] —11- (3-hydroxypropyl) ) 1 1 H-indole 1 7 1-pot lipoxamide, (R) -1- (3-hydroxypropyl) 15- [2-[[2- [2- (2,2,2-trihnoleoethoxy) phenoxy] [Ethyl] amino] propyl] — 1 H-indole-17-carboxamide, their prodrugs, and ⁇ 1 ⁇ containing at least one selected from their pharmaceutically acceptable salts — AR neutral Used as an antagonist Pharmaceutical composition, more preferably pivalic acid (R) -3- [7-potamoyl-1-5- [2-[[2- (2-(2-(2- (2-eth
  • compositions for use as an R-neutral antagonist.
  • active ingredients in these Pharmaceuticals compositions are described in WO 99/436 52 discloses, they were first found Ri by the present invention to have a 1A -AR neutral antagonist action.
  • compositions used as ⁇ 1 ⁇ —AR neutral antagonists of the present embodiment include diseases in which action as a neutral antagonist is desired, such as glaucoma, ocular hypertension, dysuria, and arrhythmia to which a normal drug is administered for a long time. And medicines and compositions such as therapeutic or preventive agents for cardiac hypertrophy, erectile dysfunction, sympathetic nervous system pain, hyperlipidemia, diabetes and the like. (3) ⁇ 1 ⁇ — Pharmaceutical composition for preventing side effects of AR inverse agonist
  • the present invention relates to a pharmaceutical composition containing o; 1A- AR neutral antagonist for preventing a 1A -AR inverse agonist from side effects.
  • “O; 1A— Side effects of AR inverse agonist” as described above refers to a rebound phenomenon in which the antagonistic action is attenuated by repeated use, the drug resistance is increased, and the symptoms are further exacerbated when the drug is withdrawn.
  • the present inventors have found that the active form mutant shed i A is dominant - was subjected to experiments by adding KRG- 3333 to AR inverse ⁇ GORE Marianist, - using CH ⁇ cells expressing AR, alpha l [alpha] Surprisingly, they have found that their inverse agonist activity is greatly diminished. Accordingly, the present invention prevents the side effects of continuous use of a 1A -AR inverse ⁇ Gore Marianist force Q! 1A -AR inverse ⁇ Gore Marianist dose can be kept low, and it even cowpea may prevent the side effects.
  • alpha l [alpha] - characterized in that it contains the AR neutral antagonist is a 1A -AR inverse ⁇ Gore Interview strike side effects prophylactic agent.
  • 1 A one AR inverse ⁇ Gore Marianist here is as described above.
  • One example of this embodiment is a pharmaceutical composition containing not only A- AR neutral antagonists, but also o; 1A -AR inverse agonists.
  • the present invention provides a method for administering a therapeutically effective amount of ⁇ 1 ⁇ -adrenergic receptor neutral antagonist to a patient receiving ⁇ 1 ⁇ -adrenergic receptor inverse agonist. And a method for preventing the side effects of ⁇ 1 ⁇ -adrenergic receptor insulin vagus in E. coli.
  • the present invention will be described in more detail with reference to the following Reference Examples, Examples and Formulation Examples, but the present invention is not limited thereto.
  • Lithium carbonate 3 Add 2.3 mL of distilled water in 120 mL of distilled water, add 120 mL of ethyl acetate, and stir with benzoic acid (R)-1- [5- (2-aminopropyl) -17-Cyanol. 2,3-dihydro-1H-indole-1-inole] propyl L-tartaric acid
  • Mutant Q! 1A AR expression ⁇ 1 ⁇ in CHO cells — Influence of candidate substance on AR expression level-human 3 ⁇ 4 1A — Threonine at 271st alanine in third intracellular loop of AR CHO cells expressing the human alpha; 1 ⁇ -AR mutant receptor, consisting of two amino acids, can be combined with pnazosin hydrochloride (Inva ⁇ Sugarust), KGR-13333 (Neutral Antagonist), or a mixture thereof cultured, their ai a - was investigated as an index of receptor expression levels the effect on AR activity.
  • human o! 1A — AR cDNA fragment the alanine of amino acid 271 of wild-type human ⁇ 1 ⁇ — AR is replaced with threonine by a modified site-specific PCR (modified site-specific PCR) method.
  • human mutant ⁇ 1 ⁇ -AR gene Human spleen 1A— receptor consisting of 466 amino acids in which the 271st alan in the 3rd intracellular loop of AR is replaced with threonine
  • wild type or mutant type 1A- AR gene is introduced into the mammalian expression vector pCR3 (Invitrogen) using the restriction enzyme EcoRI, and lipofectamine (GIBCO) is obtained. And introduced into CHO cells. Transfer the obtained cells to 500 ⁇ g / mL G
  • mutant shed 1 A - CHO cells expressing AR study drug (prepared in bunazosin or Reference Example 4 was synthesized on the basis of how the literature KGR- 333 3) (10- 8 M ) or after culturing mixtures thereof presence in 48 hours 37 ° C for (each 10- 8 M), isotonic buffer (T ris one HC 1 5 OmM, NaC 1 125m M, EDTA 2mM, pH7. 4) to The cells were collected by sonication, disrupted by sonication, and centrifuged at 80,000 xg for 30 minutes. The resulting precipitate was collected in Atsushi buffer (Tris-HC15OmM, EDTA 1 mM, pH 7.4).
  • Membrane fraction (about 20 mu ⁇ proteins tube) [3 ⁇ ] - Burazoshi (NEN) (30 to 2000 M) for 45 minutes at 30 ° C, and then use a cell collector (M-36T, Brandel) to filter the membrane fraction on a G FZC filter (Wh After washing with is-HC1 buffer (pH 7.4) several times with 5 ⁇ 1111 ⁇ , the amount of membrane-bound radioactivity was measured using a liquid scintillation counter. Non-specific binding was defined as binding in the presence of 1 / ⁇ tamsulosin hydrochloride (JP-B 62-52742). The protein quantification of the membrane fraction of the cells used was determined based on the Bradford method (Anal.
  • Figure 2 is that the active receptor predominates is i A unmutated checked - in experiments with AR, about 3-fold increase compared bunazosin hydrochloride treatment receptors amount KRG- 3333 treated with This indicates that This indicates that bunazosin hydrochloride is an inverse agonist in a 1A -AR.
  • KRG-3333 treatment did not increase receptor expression. This indicates that! 0-3333 is a new transnorre antagonist.
  • KRG-3333 and bunazosin hydrochloride were used simultaneously, the expression level of the receptor was almost unchanged.
  • KRG-3332 prepared in Reference Example 2 was dissolved in physiological saline to prepare a 0.01% solution, which was used as test solution 1 (0.01% ophthalmic solution) as follows. The descending effect was confirmed.
  • the administration of eye drops is performed twice a day at 11:00 and 19:00 twice a day with 50 ⁇ L each of the test solution in one eye and the control solution (physiological saline) in the other eye for a maximum of 57 days. It was administered continuously.
  • the intraocular pressure was measured on the first day of instillation and every week thereafter, at 11:00 (immediately before instillation), 13:00 (after 2 hours), 15:00 (after 4 hours) and 19:00 (8 At the point of time, immediately before the second instillation), the corneal surface was measured using a pneumatic applanation tonometer (Alcon Corporation) under anesthesia with 0.4% oxyproproforce in eye drops.
  • Mean value of intraocular pressure difference between test solution instillation side and control solution instillation side at each time point (mea ⁇
  • Test solution 1 KRG-3332, 0.01% eye arm
  • Intraocular pressure difference after instillation mmH g
  • KRG-3332 was dissolved in physiological saline to prepare a 0.1% solution, and this was used as test solution 2 (0.1% ophthalmic solution) to confirm the ocular hypotensive effect in the same manner as in (1) above.
  • Table 2 shows the obtained results.
  • Table 2 Test solution 2 (KRG-3332 0.1% ophthalmic solution) Intraocular pressure difference after instillation (mmH g) Table 2 shows that, similar to the above (1) 0.01% ophthalmic solution, 0.1% ophthalmic solution shows the maximum intraocular pressure drop 2 hours after instillation on any measurement day from the start of instillation to 57th day. This indicates that a significant difference was also observed here as compared with the control solution instillation group. In addition, 4 hours after instillation, a significant decrease in intraocular pressure was observed except on day 50.
  • Table 3 shows the obtained results.
  • Test solution 3 bunazosin hydrochloride 0.03% ophthalmic solution
  • Intraocular pressure difference after instillation mm H g
  • the mutant a 1A - a 1A -AR neutral antagonist does not exhibit inverse ⁇ Gore Marianist activity AR-expressing CHO cells, so as not to attenuate the intraocular pressure lowering effect by continuous administration, rebound due to drug resistance and drug suspended It can suppress or avoid the occurrence of the phenomenon, indicating that it is extremely useful as an agent for treating or preventing ocular hypertension.
  • Formulation Example 1 Eye ointment
  • a pharmaceutical composition for prevention and treatment applicable to a wide range of patients with glaucoma or ocular hypertension can be produced.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à des compositions de médicaments ayant d'excellentes propriétés, qui servent à traiter ou à prévenir les glaucomes ou les maladies associées à une hypertension oculaire et qui peuvent être utilisées en continu sur une longue période, tout en empêchant l'apparition de la tolérance au médicament causée par une administration continue. De telles compositions de médicaments, par exemple sous la forme de gouttes ophtalmologiques, se caractérisent en ce qu'elles contiennent comme principe actif un antagoniste neutre contre α1A-AR.
PCT/JP2002/007088 2001-07-13 2002-07-12 Compositions de medicaments pour usage ophtalmologique Ceased WO2003006061A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP02745996A EP1415666A4 (fr) 2001-07-13 2002-07-12 Compositions de medicaments pour usage ophtalmologique
CA002453476A CA2453476A1 (fr) 2001-07-13 2002-07-12 Compositions de medicaments pour usage ophtalmologique
US10/483,650 US20040235932A1 (en) 2001-07-13 2002-07-12 Ophthalmic pharmaceutical compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001-213624 2001-07-13
JP2001213624 2001-07-13

Publications (1)

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WO2003006061A1 true WO2003006061A1 (fr) 2003-01-23

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EP (1) EP1415666A4 (fr)
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WO2012131710A2 (fr) * 2011-03-30 2012-10-04 Panacea Biotec Ltd Nouveau procédé pour la synthèse de dérivés d'indoline

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03128332A (ja) * 1989-07-12 1991-05-31 Eisai Co Ltd α↓１―ブロッカー点眼剤
WO1995031200A1 (fr) * 1994-05-18 1995-11-23 Senju Pharmaceutical Co., Ltd. Composition pharmaceutique contenant de la terazosine, pour le traitment du glaucome
WO1999043652A1 (fr) * 1998-02-27 1999-09-02 Kissei Pharmaceutical Co., Ltd. Derives de l'indole et compositions medicales les renfermant
JP2000247998A (ja) * 1999-02-26 2000-09-12 Kissei Pharmaceut Co Ltd α１Ａアドレナリン受容体の変異体、当該変異体を用いた測定方法及び前立腺肥大に伴う排尿困難症治療剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03128332A (ja) * 1989-07-12 1991-05-31 Eisai Co Ltd α↓１―ブロッカー点眼剤
WO1995031200A1 (fr) * 1994-05-18 1995-11-23 Senju Pharmaceutical Co., Ltd. Composition pharmaceutique contenant de la terazosine, pour le traitment du glaucome
WO1999043652A1 (fr) * 1998-02-27 1999-09-02 Kissei Pharmaceutical Co., Ltd. Derives de l'indole et compositions medicales les renfermant
JP2000247998A (ja) * 1999-02-26 2000-09-12 Kissei Pharmaceut Co Ltd α１Ａアドレナリン受容体の変異体、当該変異体を用いた測定方法及び前立腺肥大に伴う排尿困難症治療剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
See also references of EP1415666A4 *
ZHAN GUI-LIN ET AL.: "Bunazosin reduces intraocular pressure in rabbits by increasing uveoscleral outflow", JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, vol. 14, no. 3, 1998, pages 217 - 228, XP002957122 *
ZHU JUN ET AL.: "Inverse agonism and neutral antagonism at a constitutively active alpha-1a adrenoceptor", BRITISH JOURNAL OF PHARMACOLOGY, vol. 131, no. 3, 2000, pages 546 - 552, XP002957121 *

Also Published As

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EP1415666A1 (fr) 2004-05-06
EP1415666A4 (fr) 2005-02-02
US20040235932A1 (en) 2004-11-25
CA2453476A1 (fr) 2003-01-23

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